1. Field of the Invention
The present invention is directed to a preservative solution suitable for preserving organs. More specifically, the invention is directed to an organ preservative solution containing a dextran having a molecular weight of 10,000 daltons or less which provides superior preservation properties.
2. Discussion of the Background
Organ transplantation has become a routine means of treating certain diseases of the organs. Transplantation requires a ready source of organs, such as kidney, pancreas, liver, heart, etc., from living persons or cadavers. Currently, most vital organs which are used for transplantation are obtained from heart beating cadavers and preserved for variable periods of time prior to their transplantation.
The two principal methods of preserving organs for transplantation are continuous pulsatile perfusion and simple hypothermic storage in a preservation solution. In pulsatile perfusion, the organ is subjected to pulsatile flow of a perfusate under hypothermic conditions such that the organ membranes receive sufficient oxygenation. Typically, the perfusate contains albumin and lipids.
With simple hypothermic storage, organs are removed from a cadaver donor and rapidly cooled. Rapid cooling is achieved by external cooling and by perfusion with a preservative solution to lower the internal temperature of the organ. The organ is then stored immersed in the preservative solution at temperatures of about 0.degree.-4.degree. C.
Significant medical advantages are achieved if organs for transplantation can be stored and preserved for 2-3 days and longer. Longer storage times provide additional time for histocapability testing of the donor and recipient, organ viability testing and provides additional time for preoperative decisions and preparations.
Numerous preservative solutions have been developed and used to preserve major organs while they are in cold storage prior to their transplantation. These preservative solutions contain a variety of compounds which act as osmotic agents to prevent cell swelling and thereby protect the organs from swelling associated cellular necrosis during storage. The degree of necrosis occurring in a stored organ can be observed by using conventional light microscopy with fixed tissue samples. More recently, the use of tandem scanning confocal microscopy (TSCM) has provided a noninvasive real time microscopic imaging technique for determining the degree of necrosis in organs (P. M. Andrews et al, Am. J. Anat., 1991, 191:95-102). Specific cell damage which can be observed includes extensive swelling and rupturing of cells and accumulation of cytoplasmic debris.
Two widely used preservative flush solutions which are commercially available are the Collins (G. M. Collins, The Lancet, 1969, 1219-1222) and the Euro-Collins (J. P. Squifflet et al, Transplant. Proc., 1981, 13:693-696) solutions. These solutions resemble intracellular fluid and contain glucose as an osmotic agent. Despite their widespread use, the Collins and Euro-Collins preservative solutions do not provide adequate preservation for storage times greater than about 48 hours. For example, kidneys stored in Collins solution for 24 hours exhibited considerable damage to the nephrons. This damage included degradation of cells lining the proximal tubules, extensive swelling and rupturing of cells lining the ascending distal tubules, degeneration of glomerular epithelial and endothelial cells and accumulation of flocculent cytoplasmic debris in the capsular spaces of Bowman. (P. M. Andrews et al, Lab. Invest., 1982, 46:100-120).
In addition to glucose, high osmolality preservative solutions have been prepared using raffinose and lactobionate as in the UW preservative solution (R. J. Ploeg et al, Transplant. Proc., 1988, 20 (suppl 1) 1:935-938), mannitol in the Sacks solution (S. A. Sacks, The Lancet, 1973, 1:1024-1028), sucrose in the phosphate buffered sucrose (PBS) preservative solution (F. T. Lam et al, Transplantation, 1989, 47:767-771) and the histidine buffered HTK solution of Bretschneider (N. M. Kallerhoff et al, Transplantation, 1985, 39:485-489). Hypertonic citrate preservative solutions are also known (H. Ross et al, Transplantation, 1976, 21:498-501). The effectiveness of these solutions as preservative solutions for organs appears to be related to the specific osmotic agent which is used (A. K. Coffey and P. M. Andrews, Transplantation, 1983, 35:136-143).
Preservative solutions are also known which contain synthetic hydroxyethyl starch (HES) as an osmotic colloid. The HES has an average molecular weight of about 150,000 to about 350,000 daltons and a degree of substitution of from about 0.4 to about 0.7. (See U.S. Pat. No. 4,879,283 and U.S. Pat. No. 15 4,798,824). U.S. Pat. No. 5,082,831 discloses a total body washout perfusion solution containing high molecular weight (500,000 daltons) hydroxyethyl starch. The HES washout solution produces substantially less edema than conventional washout solutions containing DEXTRAN 40 as a colloid. Solutions containing DEXTRAN 40 produce edema, particularly in the pancreas and lungs.
Preservative solutions are also known for preserving corneas for transplantation. Corneal preservative solutions are designed to prevent endothelial cell damage. Corneal preservative solutions containing glucose or dextran are known (H. E. Kaufman et al, Arch. Ophthalmol., 1991, 109:864-868; B. E. McCarey and H. E. Kaufman, 1974, Invest. Ophthalmol., 1974, 13:859; B. E. McCarey and H. E. Kaufman, Invest. Ophthamol., 1974, 13:165). The corneal preservative solutions known as OPTISOL, DEXSOL and MK contain DEXTRAN 40 (average molecular weight=40,000 daltons) as an osmotic agent at a concentration of 1-5 wt %. The compositions of these known solutions are shown in Table 1 below.
TABLE 1 ______________________________________ Constituents of Three Corneal Storage Media* Constituent OPTISOL DEXSOL MK K-SOL ______________________________________ Base medium Hybrid of MEM TC-199 TC-199 TC-199 and MEM Chondroitin sulfate, % 2.5 1.35 0 2.5 Dextran (molecular 1 1 5 0 weight = 40,000 d, DEXTRAN T-4O), % HEPES buffer Yes Yes Yes Yes Gentamicin sulfate Yes Yes Yes Yes Nonessential amino 0.1 0.1 0 0 acids, mmol/L Sodium bicarbonate Yes Yes Yes Yes Sodium pyruvate, 1 1 0 0 mmol/L Additional Yes Yes No No antioxidants ______________________________________ *Mem indicates minimal essential medium; TC199, tissue culture medium 199 OPTISOL and DEXSOL are manufactured by Chiron Ophthalmics, Inc., Irvine, Calif. KSOL was manufactured by Cilco Inc., Huntington, Va. but is no longer commercially available. Proprietary information, Chiron Ophthalmics.
Although many organ preservative solutions are known, these known solutions do not provide adequate preserving properties, particularly at longer storage times. Accordingly, a need continues to exist for improved organ preservative solutions capable of preserving organs for longer periods of time, thereby facilitating transplantation of these organs.